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1390 Part X: Malignant Myeloid Diseases Chapter 88: Acute Myelogenous Leukemia 1391

The myeloblasts often contain Auer rods. Marrow basophilia is present ACUTE PROMYELOCYTIC LEUKEMIA
in about half the cases. 208,280,448 The variant occurs at a younger age, has a The association of an exaggerated hemorrhagic syndrome with certain
poor prognosis, and has a tendency to trilineage dysmorphia and ringed leukemias was described by French hematologists in 1949. In 1957,
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sideroblasts. 449
Hillstad bestowed the appellation promyelocytic leukemia upon this
467
morphologic-clinical subtype of AML. This variant, which is called M3
in the FAB classification and APL in the WHO classification, occurs at
ACUTE ERYTHROID LEUKEMIA any age and constitutes approximately 7 percent of AML cases. 290,291,468,469
Prominence of erythroid cell proliferation in AML cases was noted by APL occurs with greater frequency among Latinos from Europe and
Copelli and DiGuglielmo in the early 20th century. Moeschlin South and Central America. 190,191 APL represents 19 percent of AML
450
452
451
used the term erythroleukemia. Dameshek suggested the name cases in the Chinese as compared to 8 percent among persons of Euro-
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453
DiGuglielmo syndrome and dissected the disorder into three phases, pean descent. APL is also increased among persons with an increased
depending on the decreasing prevalence of dysmorphic erythroblasts body mass index. 470–472 Unlike all other major variants of AML, which
and the reciprocal increasing prevalence of myeloblasts. Erythroid leu- increase in incidence logarithmically with age, the incidence of APL is
kemia makes up approximately 5 percent of AML cases and is referred constant over the human life span. Hemorrhagic manifestations are
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to as M6 in the FAB classification. Familial erythroleukemia has been prominent including hemoptysis, hematuria, vaginal bleeding, melena,
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described. 455,456 Erythroid leukemia is arbitrarily divided into three hematemesis, and pulmonary and intracranial bleeding, as well as the
degrees of severity: (1) erythroleukemia in which more than 50 percent more typical skin and mucous membrane bleeding. In severely leu-
of the marrow cells are dysmorphic; (2) erythroblasts admixed with kopenic patients, blasts may not be evident in the blood. Moderately
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myeloblasts, the latter composing approximately 20 percent of non- severe thrombocytopenia (<50 × 10 /L) is present in most cases. The
erythroid cells or approximately 5 to 10 percent of total marrow cells; marrow contains few agranular blast cells and some blast-like cells with
and (3) a form in which dysmorphic erythroblasts dominate the mar- scant granules. The dominant cells are promyelocytes, which comprise
row, pure erythroid leukemia, in which more than 80 percent of marrow 30 to 90 percent of marrow cells (see Fig. 88–2D and E). Auer rods and
cells are dysmorphic erythroblasts with a trivial granulocytic propor- cells with multiple Auer rods (1 to 10 percent) are present in nearly
tion of cells and very few if any myeloblasts. This last form of the disease every case. Promyelocytes with multiple Auer rods have been referred
may start in as a milder variant, formerly called erythremic myelosis, in to as faggot cells. Leukemic promyelocytes stain intensely with myelop-
which granulopoiesis, and thrombopoiesis may be only mildly abnor- eroxidase and Sudan black and express CD 9, CD13, and CD33, but not
mal. This phase, dominated morphologically by bizarre dysmorphia of CD34 or HLA-DR. 290,291,468,469
erythroblasts, can be protracted but eventually evolves into a dimorphic A variant type of promyelocytic leukemia is referred to as micro-
phase in which myeloblasts are more prominent, severe neutropenia granular (M3v in the FAB nomenclature). 473–476 Microgranular cases
and thrombocytopenia develop, and the patient progresses to erythroid represent approximately 20 percent of patients with promyelocytic
leukemia. The disease may evolve further into polyblastic AML. 457–460 leukemia. The leukemic cells may mimic promonocytes with convoluted
In the erythremic myelosis variant, erythropoiesis is ineffective. How- or lobulated nuclei. Auer rods may be present but are less evident. The
ever, some normal regulation may remain because hypertransfusion majority of the leukemic cells contain azurophilic granules that are so
decreases both erythropoietin levels and the amount of abnormal ery- small they are not visible by light microscopy, but the peroxidase stain
thropoiesis. Spontaneous growth of leukemic erythroid clonogenic usually is strongly positive. Typical hypergranulated promyelocytes usu-
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cells is a feature of the disease. Periodic acid–Schiff (PAS)-positive ally are present on careful inspection. The total white cell count often is
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erythroblasts are evident in almost all cases. 457,460 highly elevated, and severe coagulopathy is prominent in microgranular
The erythroid leukemias are characterized by a striking population cases. Rarely, the cells contain eosinophilic or basophilic granules, but
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of dysmorphic erythroblasts in marrow and red cells in blood (see Fig. t(15;17) is present, and the response to all-trans retinoic acid (ATRA)
88–2I, J, and K). Anemia and thrombocytopenia are present in nearly persists, 477–479 although the basophilic variant can be virulent. 480
all cases. Some patients may have elevated total leukocyte counts. The A translocation between chromosome 17(q21), which rearranges
red cells show marked anisocytosis, poikilocytosis, anisochromia, and the RAR-α gene at band q21, and another chromosome is present in
basophilic stippling. Nucleated red cells are present in the blood. The all cases of APL and in the acute promyelocytic transformation of
marrow erythroblasts are extremely abnormal, with giant multinucle- CML; it is not found in other AML variants. The t(15;17)(q22;q21) is
ate forms, nuclear budding, and nuclear fragmentation. Cytogenetic the most frequent cytogenetic abnormality (>95 percent), but variant
abnormalities are present in approximately 70 percent of patients and translocations between chromosome 3, 5, or 11 and chromosome 17
complex cytogenetic abnormalities are frequent. The frequency of ery- or isochromosome 17, and other even less common variants have been
throid leukemia is increased if methods for detecting erythroid dif- described. 290,468,481–483 In some cases, cytogenetic analysis is inadequate
ferentiation more sensitive than light microscopy are used. These cell and Southern blot analysis is required to identify the rearrangement
features include glycophorin A, spectrin, carbonic anhydrase I, ABH of the RAR-α gene. A functional distinction is that the t(15;17), PML–
blood group antigens, and other antigens that occur on early erythroid RAR-α fusion, the t(5:17), NPM–RAR-α fusion, and the t(3;17), TBLR1–
progenitors, such as the transferrin receptor (CD71). 463–465 Antihemo- RAR-α fusion confer retinoid therapy responsiveness, whereas t(11;17),
globin antibody and antihuman erythroleukemic cell line antibody PLZF–RAR-α fusion, usually is retinoid resistant. In cells with the
often are positive. 458 t(11;17), Auer rods are absent and CD56 expression usually is present,
Erythremic myelosis can have an indolent course and may be man- offering some clinical variables to provoke special molecular investiga-
aged for a time without intensive chemotherapy. Treatment is warranted tions. The retinoid resistance may not always be present. 485
484
in patients with erythroleukemia and acute erythroid leukemia, and the The breakpoint on chromosome 17 is within the gene encod-
results are approximately the same as with other phenotypes in patients ing the RAR-α, and the breakpoint on chromosome 15 is within the
of similar age. The more predominant the erythroid component and locus of a gene originally referred to as MYL and renamed PML (to
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the lower the proportion of myeloblasts, the better the response to indicate its relationship to promyelocytic leukemia). 290,486 The gene
therapy. 403 encodes a unique transcription factor. The translocation results in two

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